Several human disorders referred to as aryloidoses entail the accumulation and/or aggregation of misfolded proteins as a pathological characteristic and are therefore also referred to as protein-misfolding diseases. Most notably, Alzheimer's disease, Parkinson's disease and type 2 diabetes are common diseases which involve aberrant aggregation of aryloid-β (Aβ) and tau, alpha-synuclcin and Islet Amyloid Polypeptide Precursor (IAPP), respectively. [Misfolded Proteins in Alzheimer's Disease and Type II Diabetes, DeToma et al, 2012. Chem. Soc. Rev., 608-621]
The process or processes which lead to protein misfolding and aggregation is/are generally believed to be cytotoxic and as such may contribute to degeneration or failure of target cells such as neurons in the case of brain disorders such as Alzheimer's and Parkinson's disease or beta-cell function in the case of type 2 diabetes. Although neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease and metabolic disorders such as type 2 diabetes affect different tissues (respectively brain and pancreas), they have been shown to share similar risk factors [Janson J, Laedtke T, Parisi J E, O'Brien P, Petersen R C, Butler P C. Diabetes. 2004; 53:474-481]. Also the mechanism underlying the protein aggregation itself, despite the fact that it involves different proteins across different indications, has common denominators. [Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis; Rakez Kayed1, Elizabeth Head2, Jennifer L. Thompson1, Theresa M. McIntire3, Saskia C. Milton1, Carl W. Cotman2, Charles G. Glabe1; Science 18 Apr. 2003: Vol. 300 no 5618 pp. 486-489:]. These observed mechanistic commonalties between protein misfolding disorders indicate that therapeutic interventions aimed to preserve cellular integrity are expected to be efficacious over a variety of disorders which involve protein aggregation. However, the precise mechanism as to the pathways and processes involved in cellular degeneration and protein aggregation is/are still highly elusive. Therefore, in the absence of detailed mechanistic insights as to the molecular mechanism involved, the use of phenotypic assays to identify small molecules which preserve cellular integrity in cellular and animal models of aryloidosis is relevant to find effective treatments for pathients suffering aryloidoses such as Alzheimer's, Parkinson's disease and diabetes. Importantly, such treatments will alter fundamentally the course of the disease as these preserve cellular integrity of the target cells such as neurons and beta-cells and thus are expected to be disease-modifying. As such these treatments are not merely reducing temporarily disease symptoms and therefore address an important current medical need. To date, beyond diet management, medication for type 2 diabetes is focused on minimizing diabetic complications using oral hypoglycemic agents and at a later stage of the disease, insulin replacement therapy. These medications belong to four main classes:                Sulfonylureas stimulate insulin release by pancreatic β-cells. They are cheap and show little side effect, but they induce weight gain and risk of hypoglycemia and are thought to precipitate failure of insulin-producing β-cells        Biguanides (of which metformin is the reference) decrease insulin resistance and triglyceride levels. They are however inducing gastrointestinal problems and are counter-indicated for people with kidney disease or heart problems.        Alpha-glucosidase inhibitors reduce glucose absorbance by small intestine. It is however an expensive treatment with inconvenient dosing, which can induce gastrointestinal problems.        Thiazolidinediones reduce insulin resistance by activating PPAR-γ in fat and muscle. They are however expensive and associated with weight gain, increased risk of hart failure, anemia and edema.        GLP-1 analogues stimulate insulin release by pancreatic β-cells in a glucose-dependent manner, inhibit glucagon release by α-cells and slow down gastric emptying. They are expensive, need to be injected and lead to nausea.        DPP-4 inhibitors increase endogenous GLP-1 levels and exert effects similar to GLP-1 analogues. There are suggestions of an increased risk of pancreatitis and pancreatic cancer associated with the use of these drugs.        SGLT-2 inhibitors increase glucose clearance through the kidney/urine. Of this class, canagliflozin recently entered the market but is associated with side effects such as an increased desire to urinate and also associated with higher risk of vaginal yeast infections and urinary tract infections.        
Regarding neurodegenerative diseases, treatments are focused on delaying the onset, or reduce the existing symptoms. For example, cholinesterase inhibitors and/or Memantine are given to Alzheimer's pathients to delay the onset of cognitive symptoms. Levodopa is given to Parkinson's pathients to temporarily diminish motor symptoms.
There is therefore a great need for treatments which preserve and/or refunctionalize cells affected in aryloidoses to prevent the development of associated symptoms in pathients.